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P1‐241: In vivo reduction of beta‐amyloid peptides in the brain of Tg2576 mice after oral administration of a novel BACE1 inhibitor
Author(s) -
Eketjäll Susanna,
Jansson Juliette,
Eliason Kristina,
Appelkvist Paulina,
Radesäter AnnCathrin,
Jeppsson Fredrik,
Gustavsson Susanne,
Karlström Sofia,
Kolmodin Karin,
Svensson Samuel,
Fälting Johanna
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.520
Subject(s) - in vivo , pharmacology , potency , chemistry , amyloid (mycology) , in vitro , pharmacokinetics , amyloid precursor protein , amyloidosis , amyloid beta , p3 peptide , peptide , alzheimer's disease , medicine , biochemistry , biology , disease , microbiology and biotechnology , inorganic chemistry
daily for 7 days, then 16 mg daily for 7 days, followed by a co-administration period of 10 days with 125 mg avagacestat.Results: 32 and 34 subjects were randomized in the donepezil and galantamine study, respectively. Coadministration of avagacestat and donepezil or galantamine was associated with an increase in the geometric mean Cmax (14-21%) and AUC(TAU) (24-26%) of donepezil and/or galantamine; an increase not likely to be clinically relevant. One serious adverse event (SAE) was reported in healthy subjects co-administered avagacestat and galantamine for 10 days. On Day 25, a subject was found to have elevated lipase (5x ULN) and amylase (2x ULN) and was diagnosed with pancreatitis. The subject, who also had multiple gall stones, was admitted to the hospital, was treated, and recovered fully. Co-administration of avagacestat with either donepezil or galantamine in healthy subjects for short periods of timewas associated with a higher frequency of AEs than administration of donepezil or galantamine alone. The most common AEs in either study included headache, nausea, and epistaxis. Most AEs were mild in nature and all, except nasal congestion, resolved prior to study discharge. Conclusions: Co-administration of multiple 125 mg doses of avagacestat (the highest dose tested in phase IIb studies) and either donepezil or galantamine at steady-state appeared to be generally well tolerated in healthy subjects. Co-administration of avagacestat was not associated with clinically relevant increases in Cmax or AUC for either donepezil or galantamine.